Biological Activities of Acth-Analogues Varied in the Active Site

Abstract

The steroidogenic and lipolytic activities of corticotrophin-(1-24)-tetracosapeptide and [Lys17,18]corticotrophin-(1-18)-octadecapeptide amide were compared with those of corresponding analogues substituted in position 8 with norarginine and homoarginine, and in position 9 with phenylalanine and pentamethylphenylalanine. The norarginine containing analogues demonstrated a rewarding activity, although they were generally somewhat less active than the homoarginine containing compounds. This confirms the previous conclusions concerning the indispensability of arginine as a guanidinium derivate. The analogues in which phenylalanine was a substitute for tryptophan, constituted partial agonists with a low activity in steroidogenesis and lipolysis but a rather high melanophore stimulating activity. Insertion of the permethylated derivative of phenylalanine in this position, which ensures the presence of an aminoacyl residue with the full electron donor properties of tryptophan, destroyed the low steroidogenic and lipolytic activity, but increased the MSH\x=req-\ activity about 2-fold.In earlier investigations a striking difference has been found between the bio¬ logical importance of the arginyl residue in the information locus (position 8) of corticotrophic peptides and that of the arginyl residues occurring in the binding site (positions 17 and 18). Replacement of Arg17 and Arg18 by lysine